A safe and effective vaccine is needed to control the worldwide AIDS epidemic caused by the human immunodeficiency virus (HIV). The live, attenuated varicella zoster virus (VZVOka) vaccine is an attractive vaccine vector to express foreign antigens of other pathogens. It is proven safe and currently licensed for children and adults. The simian varicella virus (SVV), closely related to VZV, causes a natural, varicella-like disease in nonhuman primates. Our long term goal is to establish a novel pediatric, live, attenuated recombinant varicella-AIDS vaccine protocol to produce virus specific immunity in infants and young children, at a time when their immune systems are extremely active and well before sexual maturity to protect them against mucosal HIV infection. Our hypothesis is that a dual intranasal and subcutaneous rSVV-SIV Prime and electroporated SIV DNA Boost, with extended rest prior to SIV challenge will 1) be safe, 2) promote maximum virus specific immune responses 3) provide protection against mucosal SIV challenge without increasing SIV susceptibility and 4) preexisting SVV immunity will not diminish the vaccine induced immune responses. This hypothesis builds on our findings of specific immune responses and significantly reduced plasma SIV load following rSVV-SIV immunization and SIV intravenous challenge. In vivo electroporation of SIV DNA has been shown to stimulate immune responses, including mucosal immunity and significantly reduce SIV viremia following SIV challenge. This proposal will utilize the simian varicella and pediatric AIDS rhesus models to test the rSVV-SIV Prime, SIV DNA Boost immunization strategy and mucosal SIV challenge in SVV nave and SVV seropositive infant rhesus to define immunization route, virus specific immune responses, targeted epitopes, effects of preexisting SVV immunity, and protection against an SIV mucosal challenge. Our goal of >80% protection from infection may be better predictive of human trial outcomes. Such outcomes would hasten development of a counterpart rVZV-HIV vaccine, streamlined approvals and subsequent clinical human trials. A safe and effective pediatric rVZV-HIV vaccine would be a monumental AIDS prevention strategy, especially for children in areas of the world with endemic HIV infection.